The present invention relates to nanoparticles comprising a poorly water-soluble drug, a poorly aqueous soluble non-ionizable cellulosic polymer having an ether- or ester-linked alkyl substituent, and tocopheryl polyethylene glycol succinate (TPGS).
It is known that poorly water-soluble drugs may be formulated as nanoparticles. Nanoparticles are of interest for a variety of reasons, such as to improve the bioavailability of poorly water-soluble drugs, to provide targeted drug delivery to specific areas of the body, to reduce side effects, or to reduce pharmacokinetic variability in vivo.
A variety of approaches have been taken to formulate drugs as nanoparticles. One approach is to decrease the size of crystalline drug by grinding or milling the drug in the presence of a surface modifier. See, e.g., U.S. Pat. No. 5,145,684. Another approach to forming nanoparticles is to precipitate the drug in the presence of a film forming material such as a polymer. See, e.g., U.S. Pat. No. 5,118,528.
While these methods of forming nanoparticles are functional, nevertheless there remain a number of problems associated with the use of nanoparticles to deliver pharmaceutical compounds to the body. First, it is difficult to form very small particles. Second, once particles of the target size are formed, they must remain stable over time in a variety of different environments. Often, the nanoparticles are formed in a liquid environment. The nanoparticles must be stabilized so that they do not aggregate in solution into larger particles. In addition, the drug in the nanoparticles must be stabilized so that it does not crystallize in the use environment.
Third, the nanoparticles must be well tolerated in the body. Often surface modifiers such as surfactants are used to stabilize the nanoparticles, but such materials can have adverse physiological effects when administered in vivo. In addition, such materials are often labile, dissolving into the aqueous use environment, resulting in undesirable agglomeration of nanoparticles. Ionizable stabilizers are often not ionized in the low pH of a gastric environment, resulting in agglomeration of the nanoparticles in the stomach. In addition, without a surface modifier present, the surface of the nanoparticles is unprotected, leading to a decrease in performance and stability.
Finally, the nanoparticles must be formulated to provide optimum delivery. The nanoparticles should provide good bioavailability of the poorly water-soluble drug. In some applications, it is desired that the nanoparticles provide reduced differences in exposure when administered orally to subjects in the fed state versus in the fasted state. Alternatively, it may be desired to provide controlled or sustained release of the drug below pre-determined dissolved drug concentrations in vivo. It may be desired to administer the nanoparticles through non-oral routes, such as by parenteral, topical, or ocular delivery.
The use of TPGS as a component of nanoparticles is known in the art. See, for example, Mu and Feng (J. Controlled Release, 80 (2002) 129-144 and Pharmaceutical Research, Vol. 20, No. 11 2003, 1864-1872). In these studies, nanoparticles consisting of paclitaxel, polylactic co-glycolic acid) [PLGA], and TPGS were formed wherein the paclitaxel was in an amorphous form. However, such formulations are not ideal for commercial dosage forms.
Accordingly, there is still a continuing need for nanoparticles that are stable, in the sense of not forming crystalline drug over time or aggregating into larger particles, and that improve the bioavailability of poorly water-soluble drugs.